1 Derivatives of Carboxylic Acids Lysergic acid diethylamide (LSD)

L’imperfetto saccossa Piano piano elegge il Monglo Sastra via voi beccatori Chi pòdire è da codare? Così andiam tutti fuori, Con tutti il nostro imperfetto saccossa? … John Lennon

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5 I. Nomenclature A. Acid halides

6 I. Nomenclature B. Acid anhydrides

7 I. Nomenclature B. Acid anhydrides

8 I. Nomenclature C. Esters and lactones

9 I. Nomenclature C. Esters and lactones lactones (cyclic esters): alkanolactone (  -butyrolactone) (  -valerolactone) (  -valerolactone)

10 I. Nomenclature D. Amides, lactams, and imides

11 I. Nomenclature D. Amides, lactams, and imides (  -butyrolactam)(  -valerolactam) (  -valerolactam)

12 I. Nomenclature D. Amides, lactams, and imides succinimidemaleimidephthalimide

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14 II. Reactions B. Interconversion of functional derivatives most reactive least reactive

15 II. Reactions C. Acid halides and anhydrides

16 II. Reactions C. Acid halides and anhydrides

17 II. Reactions C. Acid halides and anhydrides

18 II. Reactions C. Acid halides and anhydrides

19 II. Reactions D. Esters Acid-catalyzed hydrolysis: reverse of Fischer esterification

20 II. Reactions D. Esters Base-promoted hydrolysis (irreversible):

21 II. Reactions D. Esters Ammonolysis:

22 II. Reactions E. Amides Hydrolysis:

23 II. Reactions F. Esters and Grignard reagents

24 II. Reactions F. Esters and Grignard reagents

25 II. Reactions G. Reduction Like carboxylic acids, esters and amides require LAH for reduction:

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TAUTOMERIA CHETOENOLICA

Tautomeria nei composti 1,3-dicarbonilici

PERCENTUALI DI FORME ENOLICHE

Acidità degli idrogeni in   The acidity of a hydrogen attached to the  - carbon of a carbonyl compound is much higher than the acidity of a typical C-H hydrogen.  pK a values range from about 19 to 20 (compared with 48 to 50) for alkanes.

Resonance stabilization of the enolate ion shifts the equilibrium Resonance stabilization of the enolate ion shifts the equilibrium to the right, thereby making the C-H bond more acidic. to the right, thereby making the C-H bond more acidic.

 Once formed, the enolate ion is capable of reacting as a nucleophile. The a-carbon of reacting as a nucleophile. The a-carbon of the enolate ion bears substantial negative charge. the enolate ion bears substantial negative charge.

Mechanism Note that the first step is rate-determining

The halogenation is difficult to stop at the mono- substitution stage. Often, poly-halogenated products are formed in this reaction.

Alkylation Reactions

The Aldol Condensation

Aldol Condensation -- Mechanism

Synthesis of an Insect Repellent

 Aldol products easily dehydrate in acid and sometimes in base. sometimes in base.

Note here that iodine is a sufficiently strong Lewis acid to bring about dehydration.

Synthesis of a Compound used in Perfumery

Crossed Aldol Condensations  Reaction of two different aldehydes:  One with an "-hydrogen (donor)  Other with no "-hydrogen (acceptor)

acceptor donor

47 Claisen Condensation  Esters also form enolate anions which participate in nucleophilic acyl substitution  As illustrated by the above example, the product of a Claisen condensation is a  -ketoester

48  Claisen condensation of ethyl propanoate gives the following  -ketoester

49 Step 1: formation of an enolate anion

50 Claisen Condensation Step 2: attack of the enolate anion on a carbonyl carbon to give a TCAI

51 Claisen Condensation Step 3: collapse of the TCAI to form a  - ketoester and an alkoxide ion

52 Claisen Condensation Step 4: formation of the enolate anion of the  - ketoester, which drives the Claisen condensation to the right

53 Dieckman Condensation  An intramolecular Claisen condensation

54 Crossed Claisen Condsns  Crossed Claisen condensations between two different esters, each with  -hydrogens, give mixtures of products and are not synthetically useful  Crossed Claisen condensations are possible, however, if there is an appreciable difference in reactivity between the two esters, for example, when one of the esters has no  -hydrogens

55 Crossed Claisen Condsns  The following esters have no  -hydrogens

56 Crossed Claisen Condsns  The ester with no  -hydrogens is generally used in excess

57 Hydrolysis and -CO 2  Saponification of a  -ketoester followed by acidification with HCl gives a  -ketoacid  Heating the  -ketoacid leads to decarboxylation

58 Claisen Condensation The result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone The result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone

59 Acetoacetic Ester Synth.  Acetoacetic ester (AAE) and other  -ketoesters are versatile starting materials for the formation of new carbon-carbon bonds because the  -hydrogens between the two carbonyls (pK a 10-11) can be removed by alkoxide bases to form an enolate anion and the  -hydrogens between the two carbonyls (pK a 10-11) can be removed by alkoxide bases to form an enolate anion and the resulting enolate anion is a nucleophile and undergoes S N 2 reactions with methyl and 1° alkyl halides,  -haloketones, and  - haloesters the resulting enolate anion is a nucleophile and undergoes S N 2 reactions with methyl and 1° alkyl halides,  -haloketones, and  - haloesters

60 Acetoacetic Ester Synth.

61 Acetoacetic Ester Synth.  The acetoacetic ester (AAE) synthesis is useful for the preparation of mono- and disubstituted acetones of the following types

62 Acetoacetic Ester Synth.  Consider the AAE synthesis of this target molecule, which is a monosubstituted acetone

63 Acetoacetic Ester Synth.  Alkylation of the enolate anion of AAE with allyl bromide forms the new carbon-carbon bond

64 Acetoacetic Ester Synth.  Saponification, acidification, and decarboxylation gives the target molecule

65 Acetoacetic Ester Synth.  To prepare a disubstituted acetone, treat the monoalkylated AAE with a second mol of base

66 Acetoacetic Ester Synth.  Then, a 2nd alkylation, saponification, acidification, and decarboxylation

67 Malonic Ester Synthesis  The strategy of a malonic ester (ME) synthesis is identical to that of an acetoacetic ester synthesis, except that the starting material is a  -diester rather than a  -ketoester

68 Malonic Ester Synthesis  Consider the synthesis of this target molecule malonic ester is first converted to its enolate anion by an alkali metal alkoxide malonic ester is first converted to its enolate anion by an alkali metal alkoxide

69 Malonic Ester Synthesis

70 Malonic Ester Synthesis  Alkylation of this enolate anion with benzyl chloride forms the new carbon-carbon bond

71 Malonic Ester Synthesis  Saponification of the diester followed by acidification and thermal decarboxylation gives the target molecule